Late effects in survivors treated for lymphoma as adolescents and young adults: a population-based analysis

Abstract

Purpose

The study objective is to describe and quantify the incidence of treatment-induced late effects in AYA lymphoma patients.

Methods

Consecutive patients diagnosed with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) at 15–24 years of age were identified. All patients in British Columbia who received radiation therapy (RT) from 1974 to 2014 with ≥ 5-year survival post-RT were included. Late effects’ analyses included only survivors who received RT to the relevant anatomical site(s) and/or relevant chemotherapy, and were reported as cumulative incidence (CI) ± standard error.

Results

Three hundred and five patients were identified (74% HL). Median age of diagnosis was 21 years. Median follow-up was 19.1 years for secondary malignancy and 7.2 years for other endpoints. Hypothyroidism was the most prevalent late effect, with a CI of 22.4 ± 2.8% and 35.1 ± 4% at 5 and 10 years, respectively. CI of in-field secondary malignancy was 0.4 ± 0.4% at 10 years and 2.8 ± 1.2% at 20 years. CI of symptomatic pulmonary toxicity was 4.6 ± 1.5% and 6.8 ± 2.0% at 5 and 10 years, respectively, and was higher in patients receiving multiple RT courses (p = 0.009). Esophageal complications occurred at a CI of 1.4 ± 0.8% at 5 years and 2.2 ± 1.1% at 10 years. CI of xerostomia/dental decay was 2.6 ± 1.3% at 5 years and 4.9 ± 2.1% at 10 years. CI of cardiac disease was at 2.3 ± 0.9% at 5 years and 4.4 ± 1.5% at 10 years. CI of infertility was 6.5 ± 1.6% at 5 years and 9.4 ± 2.1% at 10 years.

Conclusion

Survivors of AYA lymphoma have a high incidence and diverse presentation of late effects.

Implications for Cancer Survivors

AYA lymphoma survivors should be educated about their risks of late effects and offered screening and follow-up when appropriate.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Olsson DS, Andersson E, Bryngelsson I-L, Nilsson AG, Johannsson G. Excess mortality and morbidity in patients with craniopharyngioma, especially in patients with childhood onset: a population-based study in Sweden. J Clin Endocrinol Metab. 2015;100(2):467–74. https://doi.org/10.1210/jc.2014-3525.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Palmer S, Mitchell A, Thompson K, Sexton M. Unmet needs among adolescent cancer patients: a pilot study. Pall Supp Care. 2007;5(2):127–34. https://doi.org/10.1017/S1478951507070198.

    Article  Google Scholar 

  3. 3.

    Nass SJ, Beaupin LK, Demark-Wahnefried W, Fasciano K, Ganz PA, Hayes-Lattin B, et al. Identifying and addressing the needs of adolescents and young adults with cancer: summary of an Institute of Medicine Workshop. Oncologist. 2015;20(2):186–95. https://doi.org/10.1634/theoncologist.2014-0265.

    Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Gatta G, Zigon G, Capocaccia R, Coebergh JW, Desandes E, Kaatsch P, et al. Survival of European children and young adults with cancer diagnosed 1995–2002. Eur J Cancer. 2009;45(6):992–1005. https://doi.org/10.1016/j.ejca.2008.11.042.

    Article  PubMed  Google Scholar 

  5. 5.

    Barthel EM, Spencer K, Banco D, Kiernan E, Parsons S. Is the adolescent and young adult cancer survivor at risk for late effects? It depends on where you look. J Adolesc Young Adult Oncol. 2016;5(2):159–73. https://doi.org/10.1089/jayao.2015.0049.

    Article  PubMed  Google Scholar 

  6. 6.

    Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 2012;62(4):220–41. https://doi.org/10.3322/caac.21149.

    Article  PubMed  Google Scholar 

  7. 7.

    Gupta S. Adolescents and young adults with cancer and the risk of subsequent primary neoplasms: not just big children. Lancet Oncol. 2019;20(4):466–7. https://doi.org/10.1016/S1470-2045(18)30941-0.

    Article  PubMed  Google Scholar 

  8. 8.

    Robison LL, Armstrong GT, Boice JD, Chow EJ, Davies SM, Donaldson SS, et al. The Childhood Cancer Survivor Study: a National Cancer Institute–supported resource for outcome and intervention research. J Clin Oncol. 2009;27(14):2308–18. https://doi.org/10.1200/JCO.2009.22.3339.

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Youn P, Milano MT, Constine LS, Travis LB. Long-term cause-specific mortality in survivors of adolescent and young adult bone and soft tissue sarcoma: a population-based study of 28,844 patients. Cancer. 2014;120(15):2334–42. https://doi.org/10.1002/cncr.28733.

    Article  PubMed  Google Scholar 

  10. 10.

    Oeffinger KC, Tonorezos ES. The cancer is over, now what? Cancer. 2011;117(S10):2250–7. https://doi.org/10.1002/cncr.26051.

    Article  PubMed  Google Scholar 

  11. 11.

    Young people’s cancers incidence statistics. Cancer Research UK. https://www.cancerresearchuk.org/health-professional/cancer-statistics/young-people-cancers/incidence#ref-2. Published June 12, 2019. Accessed 4 Jan 2020.

  12. 12.

    Geiger AM, Castellino SM. Delineating the age ranges used to define adolescents and young adults. J Clin Oncol. 2011;29(16):e492–3. https://doi.org/10.1200/JCO.2011.35.5602.

    Article  PubMed  Google Scholar 

  13. 13.

    Smith AW, Seibel NL, Lewis DR, Albritton KH, Blair DF, Blanke CD, et al. Next steps for adolescent and young adult oncology workshop: an update on progress and recommendations for the future. Cancer. 2016;122(7):988–99. https://doi.org/10.1002/cncr.29870.

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Hay AE, Rae C, Fraser GA, Meyer RM, Abbott LS, Bevan S, et al. Accrual of adolescents and young adults with cancer to clinical trials. Curr Oncol. 2016;23(2):81–6. https://doi.org/10.3747/co.23.2925.

    Article  Google Scholar 

  15. 15.

    McBride ML, Rogers PC, Sheps SB, et al. Childhood, adolescent, and young adult cancer survivors research program of British Columbia: objectives, study design, and cohort characteristics. Pediatr Blood Cancer. 2010;55(2):324–30. https://doi.org/10.1002/pbc.22476.

    Article  PubMed  Google Scholar 

  16. 16.

    Lo AC, Samuel V, Chen B, Savage KJ, Freeman C, Goddard K (2020) Evaluation of the discussion of late effects and screening recommendations in survivors of adolescent and young adult (AYA) lymphoma. https://doi.org/10.1007/s11764-020-00922-7.

  17. 17.

    Brusamolino E, Baio A, Orlandi E, Arcaini L, Passamonti F, Griva V, et al. Long-term events in adult patients with clinical stage IA-IIA nonbulky Hodgkin’s lymphoma treated with four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine and adjuvant radiotherapy: a single-institution 15-year follow-up. Clin Cancer Res. 2006;12(21):6487–93. https://doi.org/10.1158/1078-0432.CCR-06-1420.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Morgan GW, Freeman AP, McLean RG, Jarvie BH, Giles RW. Late cardiac, thyroid, and pulmonary sequelae of mantle radiotherapy for Hodgkin’s disease. Int J Radiat Oncol Biol. 1985;11(11):1925–31. https://doi.org/10.1016/0360-3016(85)90273-1.

    CAS  Article  Google Scholar 

  19. 19.

    Thomas DM, Albritton KH, Ferrari A. Adolescent and young adult oncology: an emerging field. J Clin Oncol. 2010;28(32):4781–2. https://doi.org/10.1200/JCO.2010.30.5128.

    Article  PubMed  Google Scholar 

  20. 20.

    Gurney JG, Kadan-Lottick NS, Packer RJ, Neglia JP, Sklar CA, Punyko JA, et al. Endocrine and cardiovascular late effects among adult survivors of childhood brain tumors: Childhood Cancer Survivor Study. Cancer. 2003;97(3):663–73. https://doi.org/10.1002/cncr.11095.

    Article  PubMed  Google Scholar 

  21. 21.

    Angelini P, Rodriguez L, Zolaly M, Naqvi A, Weitzman S, Abla O, et al. Outcome and toxicity patterns in children and adolescents with non-Hodgkin lymphoma: a single institution experience. Mediterr J Hematol Infect Dis. 2017;10(1):e2018020–8. https://doi.org/10.4084/mjhid.2018.020.

    Article  Google Scholar 

  22. 22.

    Bhakta N, Liu Q, Yeo F, Baassiri M, Ehrhardt MJ, Srivastava DK, et al. Cumulative burden of cardiovascular morbidity in paediatric, adolescent, and young adult survivors of Hodgkin’s lymphoma: an analysis from the St Jude Lifetime Cohort Study. Lancet Oncol. 2016;17(9):1325–34. https://doi.org/10.1016/S1470-2045(16)30215-7.

    Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Materazzo C, Massimino M, Schiavello E, Podda M, Gandola L, Cefalo G, et al. Clinical and subclinical cardiac late effects in pediatric Hodgkin’s lymphoma survivors. Tumori J. 2017;103(6):566–71. https://doi.org/10.5301/tj.5000670.

    Article  Google Scholar 

  24. 24.

    Constine LS, Donaldson SS, McDougall IR, Cox RS, Link MP, Kaplan HS. Thyroid dysfunction after radiotherapy in children with Hodgkin’s disease. Cancer. 1984;53(4):878–83. https://doi.org/10.1002/1097-0142(19840215)53:4<878::aid-cncr2820530411>3.0.co;2-j.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Aleman BMP, Raemaekers JMM, Tirelli U, Bortolus R, van 't Veer M, Lybeert ML, et al. Involved-field radiotherapy for advanced Hodgkin’s lymphoma. N Engl J Med. 2003;348(24):2396–406. https://doi.org/10.1056/NEJMoa022628.

    Article  PubMed  Google Scholar 

  26. 26.

    Neglia JP, Friedman DL, Yasui Y, Mertens AC, Hammond S, Stovall M, et al. Second malignant neoplasms in five-year survivors of childhood cancer: childhood cancer survivor study. J Natl Cancer Inst. 2001;93(8):618–29. https://doi.org/10.1093/jnci/93.8.618.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Chemaitilly W, Mertens AC, Mitby P, Whitton J, Stovall M, Yasui Y, et al. Acute ovarian failure in the childhood cancer survivor study. J Clin Endocrinol Metab. 2006;91(5):1723–8. https://doi.org/10.1210/jc.2006-0020.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Mertens AC, Yasui Y, Liu Y, Stovall M, Hutchinson R, Ginsberg J, et al. Pulmonary complications in survivors of childhood and adolescent cancer. Cancer. 2002;95(11):2431–41. https://doi.org/10.1002/cncr.10978.

    Article  PubMed  Google Scholar 

  29. 29.

    Hahn E, Jiang H, Ng A, Bashir S, Ahmed S. Late cardiac toxicity after mediastinal radiation therapy for Hodgkin lymphoma: contributions of coronary artery and whole heart dose-volume variables to risk prediction. Int J Radiat Oncol Biol. 2017;98(5):1116–23. https://doi.org/10.1016/j.ijrobp.2017.03.026.

    Article  Google Scholar 

  30. 30.

    Aleman BMP, van den Belt-Dusebout AW, De Bruin ML, et al. Late cardiotoxicity after treatment for Hodgkin lymphoma. Blood. 2007;109(5):1878–86. https://doi.org/10.1182/blood-2006-07-034405.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Freyer DR. Transition of care for young adult survivors of childhood and adolescent cancer: rationale and approaches. J Clin Oncol. 2010;28(32):4810–8. https://doi.org/10.1200/JCO.2009.23.4278.

    Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Sadak KT, Neglia JP, Freyer DR, Harwood E. Identifying metrics of success for transitional care practices in childhood cancer survivorship: a qualitative study of survivorship providers. Pediatr Blood Cancer. 2017;64(11):e26587. https://doi.org/10.1002/pbc.26587.

    Article  Google Scholar 

  33. 33.

    Bjøro T, Holman J, Krüger Ø, Midthjell K. Prevalence of thyroid disease, thyroid dysfunction and thyroid peroxidase antibodies in a large, unselected population. The Health Study of Nord-Trùndelag (HUNT). Eur J Endocrinol. 2000;143:639–47.

    Article  Google Scholar 

  34. 34.

    Andersson A, Näslund U, Tavelin B, Enblad G, Gustavsson A, Malmer B. Long-term risk of cardiovascular disease in Hodgkin lymphoma survivors-retrospective cohort analyses and a concept for prospective intervention. Int J Cancer. 2009;124(8):1914–7. https://doi.org/10.1002/ijc.24147.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Chiu M, Austin PC, Manuel DG, Tu JV. Comparison of cardiovascular risk profiles among ethnic groups using population health surveys between 1996 and 2007. Can Med Assoc J. 2010;182(8):E301–10. https://doi.org/10.1503/cmaj.091676.

    Article  Google Scholar 

  36. 36.

    Cionini L, Pacini P, De Paola E, et al. Respiratory function tests after mantle irradiation in patients with Hodgkin’s disease. Acta Radiol Oncol. 1984;23(6):401–9. https://doi.org/10.3109/02841868409136039.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Salloum E, Tanoue LT, Wackers FJ, Zelterman D, Hu GL, Cooper DL. Assessment of cardiac and pulmonary function in adult patients with Hodgkin’s disease treated with ABVD or MOPP/ABVD plus adjuvant low-dose mediastinal irradiation. Cancer Investig. 1999;17(3):171–80. https://doi.org/10.3109/07357909909021418.

    CAS  Article  Google Scholar 

  38. 38.

    Smith LM, Mendenhall NP, Cicale MJ, Block ER, Carter RL, Million RR. Results of a prospective study evaluating the effects of mantle irradiation on pulmonary function. Int J Radiat Oncol Biol. 1989;16(1):79–84. https://doi.org/10.1016/0360-3016(89)90013-8.

    CAS  Article  Google Scholar 

  39. 39.

    Shapiro SJ, Shapiro SD, Mill WB, Campbell EJ. Prospective study of long-term pulmonary manifestations of mantle irradiation. Int J Radiat Oncol Biol. 1990;19(3):707–14. https://doi.org/10.1016/0360-3016(90)90500-j.

    CAS  Article  Google Scholar 

  40. 40.

    Villani F, Viviani S, Bonfante V, De Maria P, Soncini F, Laffranchi A. Late pulmonary effects in favorable stage I and IIA Hodgkin’s disease treated with radiotherapy alone. Am J Clin Oncol. 2000;23(1):18–21. https://doi.org/10.1097/00000421-200002000-00004.

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Villani F, De Maria P, Bonfante V, et al. Late pulmonary toxicity after treatment for Hodgkin’s disease. Anticancer Res. 1997;17(6D):4739–42.

    CAS  PubMed  Google Scholar 

  42. 42.

    Hassink EA, Souren TS, Boersma LJ, et al. Pulmonary morbidity 10-18 years after irradiation for Hodgkin’s disease. Eur J Cancer. 1993;29A(3):343–7. https://doi.org/10.1016/0959-8049(93)90382-p.

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Lund MB, Kongerud J, Nome O, Abrahamsen AF, Bjπrtuft Ø, Forfang K, et al. Lung function impairment in long-term survivors of Hodgkin’s disease. Ann Oncol. 1995;6(5):495–501. https://doi.org/10.1093/oxfordjournals.annonc.a059221.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Ellenhorn JDI, Lambroza A, Lindsley KL, Laquaglia MP. Treatment-related esophageal stricture in pediatric patients with cancer. Cancer. 1993;71(12):4084–90. https://doi.org/10.1002/1097-0142(19930615)71:12<4084::AID-CNCR2820711246>3.0.CO;2-B.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Mahboubi S, Silber JH. Radiation-induced esophageal strictures in children with cancer. Eur Radiol. 1997;7(1):119–22. https://doi.org/10.1007/s003300050123.

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Marangoni-Lopes L, Rodrigues LP, Mendonca RH, Nobre-dos SM. Radiotherapy changes salivary properties and impacts quality of life of children with Hodgkin disease. Arch Oral Biol. 2016;72:99–105. https://doi.org/10.1016/j.archoralbio.2016.08.023.

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Chang DT, Amdur RJ, Pacholke H, Mendenhall NP, Morris CG, Byer GA, et al. Xerostomia in long-term survivors of aggressive non-Hodgkin’s lymphoma of Waldeyer’s ring: a potential role for parotid-sparing techniques? Am J Clin Oncol. 2009;32(2):145–9. https://doi.org/10.1097/COC.0b013e3181841f42.

    Article  PubMed  Google Scholar 

  48. 48.

    Rodrigues NA, Killion L, Hickey G, Silver B, Martin C, Stevenson MA, et al. A prospective study of salivary gland function in lymphoma patients receiving head and neck irradiation. Int J Radiat Oncol Biol. 2009;75(4):1079–83. https://doi.org/10.1016/j.ijrobp.2008.12.053.

    Article  Google Scholar 

  49. 49.

    Koh E-S, Tran T, Heydarian M, Sachs RK, Tsang RW, Brenner DJ, et al. A comparison of mantle versus involved-field radiotherapy for Hodgkin’s lymphoma: reduction in normal tissue dose and second cancer risk. Radiat Oncol. 2007;2(1):13–1. https://doi.org/10.1186/1748-717X-2-13.

    Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Maraldo MV, Brodin NP, Aznar MC, Vogelius IR, Munck af Rosenschöld P, Petersen PM, et al. Estimated risk of cardiovascular disease and secondary cancers with modern highly conformal radiotherapy for early-stage mediastinal Hodgkin lymphoma. Ann Oncol. 2013;24(8):2113–8. https://doi.org/10.1093/annonc/mdt156.

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Campbell BA, Hornby C, Cunninghame J, Burns M, MacManus M, Ryan G, et al. Minimising critical organ irradiation in limited stage Hodgkin lymphoma: a dosimetric study of the benefit of involved node radiotherapy. Ann Oncol. 2012;23(5):1259–66. https://doi.org/10.1093/annonc/mdr439.

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Maraldo MV, Jørgensen M, Brodin NP, Aznar MC, Vogelius IR, Petersen PM, et al. The impact of involved node, involved field and mantle field radiotherapy on estimated radiation doses and risk of late effects for pediatric patients with Hodgkin lymphoma. Pediatr Blood Cancer. 2013;61(4):717–22. https://doi.org/10.1002/pbc.24861.

    Article  Google Scholar 

  53. 53.

    De Bruin ML, Sparidans J, van't Veer MB, et al. Breast cancer risk in female survivors of Hodgkin’s lymphoma: lower risk after smaller radiation volumes. J Clin Oncol. 2009;27(26):4239–46. https://doi.org/10.1200/JCO.2008.19.9174.

    Article  PubMed  Google Scholar 

  54. 54.

    Franklin J, Pluetschow A, Paus M, Specht L, Anselmo AP, Aviles A, et al. Second malignancy risk associated with treatment of Hodgkin’s lymphoma: meta-analysis of the randomised trials. Ann Oncol. 2006;17(12):1749–60. https://doi.org/10.1093/annonc/mdl302.

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Draube A, Behringer K, Diehl V. German Hodgkin’s Lymphoma Study Group trials: lessons from the past and current strategies. Clin Lymphoma Myeloma. 2011;6(6):458–68. https://doi.org/10.3816/CLM.2006.n.026.

    Article  Google Scholar 

  56. 56.

    Shanbhag S, Ambinder RF. Hodgkin lymphoma: a review and update on recent progress. CA Cancer J Clin. 2017;68(2):116–32. https://doi.org/10.3322/caac.21438.

    Article  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Zhou R, Ng A, Constine LS, Stovall M, Armstrong GT, Neglia JP, et al. A comparative evaluation of Normal tissue doses for patients receiving radiation therapy for Hodgkin lymphoma on the childhood Cancer Survivor Study and Recent Children’s Oncology Group Trials. Int J Radiat Oncol Biol. 2016;95:1–5. https://doi.org/10.1016/j.ijrobp.2016.01.053.

    Article  Google Scholar 

  58. 58.

    Ansell SM. Maintaining efficacy but decreasing toxicity in the treatment of Hodgkin lymphoma. HemaSphere. 2017;1(1):e7–2. https://doi.org/10.1097/HS9.0000000000000007.

    Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Children’s Oncology Group: long-term follow-up guidelines for survivors of childhood, adolescent and young adult cancers, Version 5.0. 2018:1–232. http://www.survivorshipguidelines.org/. Accessed 01 Sep 2020.

Download references

Author information

Affiliations

Authors

Contributions

Conceptualization: Karen Goddard, Andrea C. Lo; Methodology: Andrea C. Lo, Ben Chen, Vanessa Samuel, Kerry J. Savage, Ciara Freeman, Karen Goddard; formal analysis and investigation: Ben Chen; writing—original draft: Andrea C. Lo, Ben Chen; writing—review and editing: Andrea Lo, Ben Chen, Vanessa Samuel, Karen Goddard, Kerry J. Savage, Ciara Freeman; supervision: Andrea C. Lo, Karen Goddard.

Corresponding author

Correspondence to Andrea C. Lo.

Ethics declarations

Conflict of interest

K.J.S received institutional research funding from Roche. C.F. has honoraria from Seattle Genetics, Janssen, Amgen, Celgene and Abbvie, and research funding from Roche and Teva. None of the other authors have conflicts of interest to disclose.

Ethics approval

This study was approved by the University of BC / BC Cancer Research Ethics Board.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

ESM 1

(DOCX 411 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lo, A.C., Chen, B., Samuel, V. et al. Late effects in survivors treated for lymphoma as adolescents and young adults: a population-based analysis. J Cancer Surviv (2021). https://doi.org/10.1007/s11764-020-00976-7

Download citation

Keywords

  • Lymphoma
  • Radiation therapy
  • Radiotherapy
  • Late effects
  • Toxicities
  • Adolescent and young adult